This SBIR Phase II work will seek to develop and optimize reagents for the radioimmunotherapy of cancer using bispecific antibody pretargeting. The bispecific antibodies that we will make will have the dual advantages of being low-immunogenic humanized proteins, and will be preparable in high yield after enhancement of transfected cell lines. They will be targeted in human tumor xenograft-bearing mice, to determine preferred times and doses to maximize tumor uptake and minimize normal tissue retention. The second arm of the tumor-localized bispecific antibody will be specific for a radioimmunotherapeutic comprised of a rhenium-188- radiolabeled peptide, that clears living systems rapidly, if not bound by tumor-appended bispecific antibody. Doses and timings of injections of the radioimmunotherapeutic will be optimized, after animals have been pretargeted with the bispecific antibody. After optimization of all parameters, preclinical radioimmunotherapy studies and dosimetry determinations will be done. Using knowledge gained from the preclinical animal work, the developed agents will be tested in a Phase I clinical trial, using the corresponding technetium-99m-labeled recognition peptide as a model for the rhenium-188 version. With promising data from the Phase I clinical trials, we will proceed to radioimmunotherapy in a Phase I/II clinical trial if the results so merit. PROPOSED COMMERCIAL APPLICATIONS: Radioimmunotherapy using bispecific antibody in a pretargeting approach has the advantage of being capable of high dose delivery of radiation to tumor sites without significant retention in normal organs, maximizing the therapeutic potential of the treatment modality. Patients will be injected with the nontoxic bispecific antibody first, and after the predetermined time for localization and clearance, therapeutic Re-188 labeled peptide will be administered to achieve a therapeutic response.